(2) HIV Clinical Manifestations Flashcards
What is the primary HIV infection?
Acute Retroviral syndrome - HIV infection PRIOR to seroconversion
How does acute retroviral syndrome present?
o Fever o Sweats o Malaise o Myalgias o Anorexia o Nausea o Diarrhea o Non-exudative pharyngitis
When does Acute Retroviral Syndrome occur?
- Onset 1-6 weeks from exposure – peaks at 3 weeks
* Symptoms generally resolve in 10-15 days
What is the window period?
= patient infected but antibodies not yet detected- they have a high viral load, very infectious to others, but cant detect HIV on an ELISA (remains negative for 2-6 weeks after onset of symptoms)
How does the Lab evaluate ARS?
Detection of HIV specific antibodies in plasma or serum : HIV antibodies = seroconversion
• Appear a few weeks after infection o 5% within 7 days o 50% within 20 days o 95% within 90 days why we test after 4 weeks, 3 months
What are the laboratory characteristics to look for in someone with suspected HIV?
Reduced total lymphocyte count (lymphopenia followed by lymphocytosis from expanded CD8 cells).
CD4 count plummets (CD4:CD8 ratio is inverted)
HIV p24 antigen - detected in 75% of people in serum or CSF within 2 weeks of exposure
HIV RNA markedly elevated in most patients
ELISA for HIV antibodies remains negative for 2-6 weeks after onset of symptoms
Anti-p24 appears on the western blot first
What is the standard screening test for HIV?
ELISA
HIV antigens exposed to & bound by HIV antibodies in serum
Presence detected by second anti-human antibody
HIV 1&2 in most commercial kits
->+ve in 3-6 weeks
When can you get a false positive ELISA?
Recent immunisation (HBV, Influenza) Autoimmune disease Pregnancy (due to antibodies to HLA antigens) Multiple myeloma End stage renal failure
When can you get false negative ELISA
WIndow period
- acute infection prior to antibody development
- HIV-2 N or 0 group infections
- Hypogammaglobulinemia
When do you do a western blot?
TO confirm a positive ELISA
What does a Western blot show?
Detects antibodies in patients sera that react with a number of different viral proteins ->Uses gel electrophoresis to detect proteins
HIV proteins are first separated by electrophoresis, Then blotted onto nitrocellulose membrane, The membrane is incubated with patients serum ->Specific antibodies fix to the respective HIV proteins ->Produces coloured band after colouring reaction
Distinct bands of different molecular weight using protein gel electrophoresis
Positive if all 3 groups:
- > Gag p24 (usually first)
- > Envelope proteins – gp160, gp120, gp41 (second)
- > Polymerase proteins – p66 or p51
What are the clinical symptoms of ARS?
• Often there is a maculopapular, diffuse rash – involves face, neck and trunk
o Can be misdiagnosed: meningococcal, drug reactions, viral infections
How do we treat ARS?
Reduce symptoms & transmission
ART recommended for all persons with HIV infection & should be offered to those with early HIV infection.
All pregnant women with early HIV infection should start ART as soon as possible to prevent perinatal transmission of HIV to baby ->is some concern re affect of ART on baby, but bad affects occur in first 5-6 weeks before they know they are pregnant
If treatment is initiated in a patient with early HIV infection, the goal is to suppress plasma HIV RNA to below detectable levels
For patients with early HIV infection in whom therapy is initiated, testing for plasma HIV RNA levels, CD4 count, and toxicity monitoring should be performed as described for patients with chronic HIV infection
What are some of the clinical manifestations of HIV?
Persistant generalised lymphadenopathy
Oral Disease(OHL, candida infection, gingovitis, peridonditis, oral ulcers, KS, non hodkins lymphoma)
VZV
What is PGL (Persistant generalised lymphadenopathy)
Pathogenesis
Definition
Seen in 75% of infected individuals
Pathogenesis: rapid infection of CD4 cell in lymph nodes by HIV after initial infection
Defined as presence of 2 or more sites of extra inguinal lymphadenopathy for a minimum of 3-6 months for which no other explanation can be found.
In HIV - usually symmetrical, 0.5-2cm, mobile and rubbery
What are the differentials you would want to discount in diagnosing someone with persistant generalised lymphadenopathy?
• Differentials – o Sarcoid o Secondary syphilis o Hodgkins lymphoma o Mycobacteria o KS o Lymphoma o Castleman’s disease (angioproliferative hyperplastic process of lymph nodes)
When would you see a candida infection (oral thrush)?
How would you treat it?
Differentiate as you can scrape these off
- white plaques over the hard and soft palates, buccal mucosa, tongue, pharynx and hypopharynx
- seen more commonly when CD4 falls below 200-300.
- Diagnosis often made by appearance alone.
- Often accompanied by candida oesophagitis = AIDS defining illness
- Treated with FLUCONAZOLE
When would you see Oral hairy leukoplakia?
What would you want to discount from your diagnosis?
Oral Hairy Leukoplakia (OHL) - Associated with EBV - Diagnosed o On visual inspection o Inability to scrape off o *Failure to respond to antifungals o And on biopsy • Treatment o Restoring the immune system
Other oral diseases
Severe gingivitis & periodontitis (foul smelling)
o Must be taken seriously – rapid gum loss
- Oral ulcers
- KS – blue/red papules in the back of the mouth
- NHL (non-hodgkins lymphoma)
When would you see VZV?
Treatment?
20-30x more common in patients with HIV
May cross between dermatomes in patients with HIV
• VZV much more common in patients with HIV (12-30%)
Disseminated zoster >10 cutaneous lesions
Treatment = Valaciclovir
In severe immunosuppression IV acyclovir may be preferred
o Infection control – keep isolated (if its just cutaneous – cover the lesion)
What happens to your CD4 count over the years?
CD4 – lose 50-70 cells per year
Advanced HIV more at risk of opportunistic infections (late stage disease CD4 <200)
Name some advanced infections which are AIDs defining:
Bacteria
- Mycobacterium avium complex
- Mycobacterium kansasii (disseminated/extrapulmonary)
- Mycobacterium tuberculosis
- Mycobacterium (other) – disseminated/extrapulmonary
- Salmonella (recurrent sepsis)
Name some advanced infections which are AIDs defining: FUNGAL
Candidiasis – bronchial, oesophageal, tracheal, pulmonary
Coccidioidomycosis – disseminated/extrapulmonary (America not Aus)
Cryptococcus – extrapulmonary
Histoplasmosis – disseminated/extrapulmonary
Pneumonitis jiroveci – pneumonia
Name some advanced infections which are AIDs defining: Protozoan
- Cryptosporidiosis (intestinal, >1 month)
- Isosporiasis (intestinal, >1 month)
- Toxoplasmosis (brain)
Name some advanced infections which are AIDs defining: Viral
- Cytomegalovirus (other than liver, spleen or nodes)
* Herpes simplex virus (chronic ulcers >1 month or oesophagitis, bronchitis, pneumonitis)
Name some advanced infections which are AIDs defining:Malignancies
- Cervical cancer (invasive)
- Kaposi’s sarcoma
- Lymphoma (Burkitt’s, immunoblastic, brain primary)
Name some advanced infections which are AIDs defining: OTHER
- Encephalopathy (HIV)
- Progressive multifocal leukoencephalopathy
- Pneumonia (≥2 episodes in 12/12)
- Wasting syndrome >10% LOW or fever or weakness >30 days
What defines ‘late stage HIV’?
- CD4 <200
* Susceptible to opportunistic infections
For differential diagnosis’ according to presentation of COUGH & pulmonary infiltrate + CD4 count check notes
check notes.
What is PJP?
Pneumocystis jirovecii is the most common opportunistic infection in persons with HIV infection.
Implicated cause of interstitial plasma cell pneumonia in immunosuppressed
Unicellular fungi deposits in alveoli
Infants natural host for the disease – colonized in first few months of life → acquired early in life
Reactivation causes intra-alveolar pneumonitis (life threatening)
If CD4 <200 cells/mm3
What are the clinical features of PJP?
o Subacute insidious onset 2-4 weeks o Band-like tightness around thorax o Dry cough (non productive) o Febrile o SOB
What investigations would you do in someone with PJP?
- > Low SaO2
- > Bilateral & often diffuse interstitial shadowing on CXR (often spares lower zones)
->Up to 20% of patients will have –ve CXR but can CT scan, which will confirm positive findings
o Elevated LDH
o CD4 <250
What would you find radiographically in someone with PJP?
Typical classical presentation
Diffuse, interstitial, reticular, bilateral infiltrates in butterfly pattern
Usually in HIV spares the lower lobes (can see diaphragms)
The great imitator • Nodules • Lobar infiltrates • Alveolar infiltrates, cavities, UL predominance • Asymmetric patterns
HOW DO YOU confirm the diagnosis of PJP?
By demonstration of P carinii cysts by immunofluorescence or PCR in induced sputum or BAL fluid
Induced sputum in HIV: 55-97% sensitivity
Bronchoscopy: 95-99% sensitivity (PCP- deposited in alveoli)
o Open lung Bx or VATS: 95-100% sensitivity = rarely needed
How do you treat PJP?
High dose co-trimoxazole 2DS tab q8h
Or pentamidine
Clindamycin 600mg 8/24 plus primaquine 30mg daily
Dapsone 100mg daily plus trimethoprim 5mg/kg tds
Atovaquone 750mg bd also effective
o Note → must give adjunctive prednisolone if PaO2 <70mmHg
• 40mg bd 5/7, 40mg daily 5/7, then 20mg daily for 11 days
what is the most common neoplasm affecting HIV individuals?
Kapowsi’s sarcoma
What Is it implicated with?
Vascular neoplastic disorder
HHV8 implicated in pathogenesis → MCQ question
Cutaneous red-purple nodules or plaques
What is the most common site for Kapowsi’s sarcoma
Skin is the most common site
o Painless non-pruritic firm nodular tumours usually violaceous in colour
What happens when Kapowsi’s sarcoma involves pulmonary ?
• Pulmonary involvement may be fatal
o Reticulonodular infiltrates with perihilar distribution
o Hilar lymphadenopathy
o Pleural effusions occasionally
Which growth factors promote/play a role in the pathogenesis of Kawposi’s sarcoma pathogenesis?
HIV Tat protein
Basic fibroblast growth factor
Numerous cytokines
What is the usual Mode of transmission for Kawposi’s sarcoma?
In endemic areas transmission occurs through saliva & in epidemic areas – sexual transmission is the mode of acquisition
Usually in MSM
what is the clinical presentation of Kawposi;s sarcoma?
Clinical presentation differs according to the KS variant
- The tip of the nose (and penis) are the typical places for it
How do you diagnose Kawposi’s sarcoma?
BIOPSY
Histology – fusiform cells & vascular spaces filled with erythrocytes
How do you manage Kawposi’s sarcoma?
No definitive KS guidelines
• Localised radiation
• Severe disease – systemic chemotherapy with liposomal doxorubicin or vincristine plus bleomycin or alpha-interferon
CASE:
55 y.o. female – migrant from Sudan (6 years ago)
- >CD4 count 23, VL >100,000
Has never had ART
• Presents with:
Fever, Weakness, Fatigue, Dairrhoea, Abdominal pain, Weight loss, Dyspnoea on exertion, Dry cough for 2 weeks
WHAT IS YOUR DIFFERENTIAL?
o PCP (not usually diarrhea)
o Pulmonary KS maybe
o Mycobacterium Avium Complex disease***
What is Mycobacterium Avium Complex Disease?
What is CD4 count around?
What is the incidence in those HIV AIDs without prophylaxis?
Ubiquitous in environment - pulmonary disease
• Most disease occurs with CD4 <50
• Incidence 20-40% within 2 years of AIDS diagnosis without prophylaxis
o Seen in patients with resistant HIV & those presenting late to care
• Independent predictor of mortality in AIDS
What are the clinical features of Mycobacterium Avium Complex disease?
Causes fever, night sweats, abdominal pain, diarrhea, fatigue & weight loss
Examination may demonstrate hepatosplenomegaly & diffuse lymphadenopathy
Patients have a continuous bacteraemia
How do we diagnose Mycobacterium Avium Complex Disease?
By isolation of mycobacterium from a blood culture
o Histology - macrophages filled with mycobacterium (acid filled bacilli)
How do we treat Mycobacterium Avium Complex Disease
–>Use at least 2 drugs as initial therapy
Clarithromycin, Ethambutol - must do colour vision testing (side effect is loss of colour vision)
o Consider adding rifabutin
o Duration – lifelong unless immune recovery on HAART
CASE :
- > 39y.o. male, CD4 115
- > PC: Headache, cough, low grade fever, 4kg weight loss
- > No meningitic signs, no papilloedema
- > Lumbar Puncture performed:
- 35 WBC, 90% lymphocytes (viral)
- Protein raised 0.57, glucose 5.5
- Serum & CSF cryptococcal antigen positive
- whats wrong?
??
Cryptococcal meningitis
Approach to a HIV infected patient with a headache
DO a CD4 count
Approach to a HIV infected patient with a headache & CD4 > 200
What are the differentials?
Tension Migraine Cluster Hypertension Medications Sinusitis Pyogenic meningitis HSV meningitis/encephalitis VZV meningoencephalitis Neurosyphillis
Approach to a HIV infected patient with a headache & CD4 < 200
What are the differentials?
Cerebral toxoplasmosis Cryptococcal meningitis CNS lymphoma Listeria monocytogenes TB meningitis CMV meningoencephalitis HSV/VZV meningoencephalitis Neurosyphilis PML
What is Cryptococcal Meningitis?
Caused by Cryptococcus neoformans; rarely by Cryptococcus var gatti in Australia
Fungal infection
Meningitis often presents subacutely & needs to be differentiated from other causes of CNS impairment
If patients dont recieve HAART, how many will get cryptococcal meningitis?
Pre-HAART: 5-8% of patients with AIDS developed disseminated cryptococcosis
With HAART (Highly Active Antiretorviral Therapy) – incidence decreased *NOTE WILL NOT HAVE NECK STIFFNESS
Poor outcomes for Cryptococcal meningitis are associated with-
Poor outcome is associated with:
o Raised ICP
o Poor mentation initially
o High CSF cryptoccal Ag
How do we diagnose cryptococcal meningitis?
Seen in CSF by india ink staining
Isolation of organism
By culture or cryptococcal antigen detection
Measuring antigen titre is useful in monitoring response to treatment & to monitor relapse
Most common cause of meningitis in AIDS patients with CD4<100
How do we treat cryptococcal meningitis?
Initial therapy with amphotericin B & flucytosine
Amphotericin – side effects: hypokalemia, hypomagnesia (toxic to kidneys)
Fluconazole maintenance
TAP EARLY & TAP OFTEN
o 93% of deaths in the initial 2 week are due to elevated ICP
What are HIV AIDS patients vulnerable to when their CD4 drops below 50?
CYTOMEGALOVIRUS which is a Multisystem disease including: o Retinitis o Leucopenia o Hepatitis o Pneumonitis o Oesophagitis o Colitis – profuse watery diarrhea o Painful peripheral neuropathy o Encephalitis
How do we treat Cytomegallovirus?
Ganiciclovir/foscarnet/cidofovir/valganciclovir
CMV retinitis can cause blindness- what are the subacute signs
Vision symptoms are subacute in onset: • Blurred vision • Scotomas • Floaters • Flashing lights
Retinal finders are characteristic
• Mix of exudates, haemorrhages & atrophy
• Vascular sheathing
• Treatment is to prevent blindness & retinal detachment
What is the most common cause of INTRACRANIAL MASS LESIONS in HIV AIDS sufferers?
Cerebral Toxoplasmosis
How would we diagnose cerebral toxoplasmosis, what is the CD4 count usually?
<200
Diagnosis:
CT SCAN features include multiple contrast enhanced ring enhancing lesions
MRI scans are more sensitive
PCR testing CSF confirmatory.
How do we treat cerebral toxoplasmosis
Treatment
- Initiation of therapy usually empirical
- Pyrimethamine plus sulfadiazine plus folinic acid
- Follow up CT/MRI at 2 weeks should demonstrate improvement (lesions should be getting smallers)
When a patient presents with fever, headaches and right sided weakness, what is a likely diagnosis?
Progressive Multifocal Leukoencephalopathy - due to reactivation of polyomavirus infection (JC virus)
What is the histological features of progressive multifocal leukoencephaly?
Clinical features?
When is the primary infection aqcuired in childhood.
demyelination of oligodendrocytes causing
Dementia/aphasia/motor deficits
• Primary infection acquired in childhood
• CNS infection causes multiple white matter lesions – hyperintense T2 images in subcortical regions
How do we diagnose progressive multifocal leukoencephaly?
PCR testing in CSF
CNS infection causes multiple white matter lesions – hyperintense T2 images in subcortical regions
How do we treat progressive multifocal leukoencephaly?
Respond to cidofovir or cytosine arabinoside therapy
o Treatment with HAART
What are some other clinical problems that HIV sufferers experience?
- LOOK AT SUMMARY SHEET FOR INFO ON PROTOZOAN/BACT/VIRUSES that CAUSE THESE THINGS** Diarrhoea HIV Associated Nephropathy (HIVAN) Hep B & C co-infection HIV-1 Associated Neurocognitive Disorder
Name some sites of drug action used for HIV treatment
Fusiion/entry inhibitors
Reverse transcriptase inhibitors
Integrase inhibitors
Protease inhibitors
All drugs in HIV have side effects.
What are some minor side effects experienced?
Minor
• Nausea
• Vomiting
• Diarrhea
All drugs in HIV have side effects.
What are some major side effects experienced?
Pancreatitis Peripheral neuropathy Hepatic impairment Hypersensitivity reactions Lipodystrophy syndrome Metabolic Syndrome
What is lipodystrophy syndrome
Redistribution of body fat Hyperlipidemia Glucose intolerance Seen most often in association with protease inhibitors Not as bad with new ARTs
What are the features of metabolic syndrome?
Pathogenic mechanisms?
Diagnosis?
Treatment?
Features: • Dyslipidemia • Hypertriglyceridemia • Depressed concentrations of HDL • Elevated LDL Pathogenic mechanisms • Virus itself • Effects of ART on key metabolic pathways • Drug associated adipose repartitioning with subsequent development of insulin resistance & associated metabolic derangements Diagnosis – fasting lipid profile Treatment • Changes to diet & lifestyle • Consider switching ART if possible • Statin drugs (interaction with CYP3A4 pathway) – fibrates • Don’t give simvastatin to someone with HIV • Management of co-morbidities
What is the life expectancy on ART?
- HAART – mortality is much lower
* Life expectancy Aus male ~79, so someone diagnosed with HIV in 20’s/30s – live to about 60/65
Treatment for ART?
Ratonavir – boosts other ART therapies (protease inhibitors) so you get higher levels without the side effects of the drugs
Raltegravir – few drug interactions, few side effects
Duranavir – well tolerated
What should you think about when someone is commencing ART?
- Clinical Assessment
- Social context
- Depression/drug use
- Laboratory investigation
- Investigation of comorbidities
- Health maintenance
- Education and support
What do you need to check before commencing ART?
Hep B & C status Syphilis serology CD4 & HIV VL HIV genotype Baseline FBC, EUC, LFT HLA B5701 CMV/Toxoplasmosis serology Consider mantoux/CXR
What are the current guidelines for HIV treatment?
Backbone of 2 x NRTI (nucleotide reverse transcriptase inhibitors)
Plus 1 x non nucleoside reverse transcriptase inhibitors or boosted PI
Under no circumstances should therapy be with a single agent
In summary what needs to be done?
- Monitor Viral load, CD4 count and clinical status
- Use a multidrug regimen
- Monitor efficacy by serial viral load measurement
- Side effects may be life threatening
- Drug resistant variants may eventually emerge
- Consider appropriate use of prophylactic therapy for opportunistic infections
